N-benzoyl-
staurosporine (
PKC412) is a selective inhibitor of
protein kinase C, and it inhibits the growth of human
cancer cells. In this study, we examined the antitumor effect of
PKC412, given singly and in combination with
paclitaxel, on
tumor regression and chemotherapeutic side effects by assessing
tumor burden and
cytokine production responses in vivo. Twenty-six nude mice intraperitoneally inoculated with SKOV3 cells were treated differently in 4 treatment groups:
PKC412 plus
paclitaxel (n = 7),
paclitaxel-only (n = 6), PKC412-only (n = 6), and controls (n = 7). At autopsy, we found that
PKC412 itself slightly reduced the mass of
tumor but did not fully inhibit
tumor formation. The incidence of evident disease was decreased when
PKC412 was combined with
paclitaxel (43%). From the
body weight of the
tumor-bearing mice, we observed that
PKC412 plus
paclitaxel treated mice were less wasted than
paclitaxel-only treated mice (18.1 g vs 22.4 g, p = 0.001). We measured intracellular
TNFalpha, IFNgamma,
IL-4, and
IL-10 in stimulated mouse splenocytes using flow cytometry to determine if
PKC412 inhibited
cytokine production in T cells.
TNFalpha, IFNgamma, and
IL-10 production were all significantly inhibited in the
paclitaxel-treated mice. The inhibitory effects on
cytokine production by
paclitaxel were compensated with
PKC412 combination (p = 0.008, 0.035, 0.014, respectively). From this study, we deduce that
PKC412 may have clinical applications in promoting
tumor regression in
ovarian cancer when combined with
paclitaxel. Moreover,
PKC412 is able to prevent
weight loss and immunosuppression induced by
paclitaxel because it rescues normal proliferating cells from cytotoxic effects.